A Study of the Safety and Efficacy of Prime Editing (PM647a) in Participants With Alpha-1 Antitrypsin Deficiency

NCT07887347 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: Prime-0301
• Study Type: interventional
• Target: 54
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this study is to evaluate the safety, tolerability, biological activity, and initial efficacy of PM647a, an investigational Prime Editing therapy, in adults and adolescents with Alpha-1 Antitrypsin Deficiency (AATD). AATD is caused by a mutation (change) in a gene called SERPINA1 that prevents the cells in your liver from producing a functional protein (alpha-1 anti-trypsin; AAT) that helps protect your lung tissue. PM647a is designed to precisely correct the prevalent disease-causing mutation (SERPINA1 Pi\*Z (E342K)) with the goal of restoring functional AAT. This is the first study of PM647a in humans. Participants will receive a single intravenous (IV) infusion of PM647a and will be monitored closely to evaluate safety, how the body responds to treatment, changes in AAT protein levels, and whether treatment may improve signs and symptoms of AATD.

Conditions

Alpha-1 Antitrypsin Deficiency; Alpha-1 Antitrypsin Deficiency-associated Lung Disease; Alpha-1 Antitrypsin Deficiency (AATD); AATD

Keywords

gene therapy; gene editing; Prime Editing; PM647a; SERPINA1; AATD; Pi*ZZ; Pi*Z

Outcome Measures

Primary Outcomes (1)

• Safety and tolerability of PM647a. Quantified by frequency and severity of treatment emergent adverse events (TEAEs)

  Immediately post-infusion up to Week 48

Secondary Outcomes (17)

• Frequency and severity of Dose Limiting Toxicities (DLTs)

  Infusion up to and including 28 days

• Percentage of participants with ≥ 11 µM total serum alpha-1 antitrypsin (AAT) levels

  Week 12 post-infusion

• Percentage of participants with ≥ 11 µM total serum AAT levels

  Week 4, Week 6, Week 12, Week 24 and Week 48 post-infusion

• Percentage of participants with total serum AAT levels ≥ the lower limit of normal

  Week 4, Week 6, Week 12, Week 24 and Week 48 post-infusion

• Change in total serum AAT levels, including changes in levels of pathogenic AAT (Z-AAT) and normal (M-AAT)

  Baseline to Week 4, Week 6, Week 12, Week 24, and Week 48 post-infusion

Study Arms (1)

PM647a

EXPERIMENTAL

PM647a is a sterile suspension of lipid nanoparticle (LNP)-formulated Prime Editors (PEs) intended for single dose intravenous (IV) infusion for the treatment of Alpha-1 Antitrypsin Deficiency (AATD)

Drug: PM647a

Interventions

PM647a DRUG

PM647a is being evaluated in participants with Alpha-1 Antitrypsin Deficiency (AATD) caused by a homozygous Pi\*Z allele (Pi\*ZZ genotype), with an observed lung phenotype (Group A), or an observed liver and lung or liver alone phenotype (Group B)

PM647a

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants at least 18 years of age at the time of consent and able to provide written consent
• Confirmed diagnosis of AATD as determined by medical history consistent with AATD, and diagnostic genetic testing performed by the designated central laboratory demonstrating homozygous presence of the SERPINA1 Pi\*Z (E342K) allele
• Blood total AAT level \< 11 μM or history of total AAT levels \< 11 μM
• a) For individuals receiving augmentation therapy, willingness to stop augmentation therapy for at least 5 half-lives or 4 weeks, whichever is longer, prior to the planned infusion of PM647a through Week 16 post-PM647a infusion
• Group A only: Postbronchodilator FEV1 ≥ 30% of predicted (or ≥ 40% of predicted for participants on augmentation therapy) and at least ONE of the following:
• FEV1/FVC \<70% at screening OR
• Annualized decline in post-bronchodilator FEV1 of ≥100 mL, calculated from at least two spirometry assessments obtained at least 12 months apart
• Group A only: Radiologic or physiologic evidence of emphysema (obtained within 6 months of signing the ICF) defined as either:
• Chest CT imaging demonstrating a clinically significant burden of emphysematous change consistent with AATD-related disease (as judged by the Investigator or interpreting radiologist)
• DLCO ≤70% predicted (corrected for anemia, if present)
• Willingness to abstain from alcohol use and herbal medications from the start of the screening period through 28 days post-PM647a administration
• Willingness to avoid strenuous physical activity starting 1 week prior to PM647a infusion through 14 days after PM647a infusion
• Willingness to participate in a long-term extension study with the understanding that the total duration of participation is 15 years post-infusion
• Group B only: Liver histopathologic examination with a METAVIR fibrosis stage of F1, F2, or F3
• Group B only: FibroScan ≤12 kPa

You may not qualify if:

• Prior medically significant reaction to an LNP-based or PEG-containing product medication (e.g., severe hypersensitivity reaction, myocarditis)
• Use of any investigational product within 30 days (or 5 half-lives, whichever is longer) of signing ICF
• Prior receipt of genetic medicine for AATD
• History of lung or liver transplantation, or actively waitlisted,
• History of lung volume reduction surgery (LVRS) or endobronchial lung volume reduction (ELVR)
• Recent (within past 6 weeks) COPD exacerbation requiring antibiotic or steroid therapy, or requiring hospitalization
• Resting SpO2 ≤88% on room air or requiring \> 3 L/min supplemental oxygen to maintain SpO2 \> 88%
• Body mass index (BMI) \>35
• Current or recent regular smoking history (within the past 12 months) or not willing to abstain from smoking (including vaporizers/e-cigarettes, marijuana) for the duration of the study
• Liver disease with any of the following:
• Total bilirubin \> 1.5 x ULN at screening, except for participants with documented Gilbert's Syndrome
• Decompensated cirrhosis or advanced liver disease
• Model for End-Stage Liver Disease (MELD) score \> 13
• Group A only additional requirements:
• ALT or AST \>1.5x upper limit of normal (ULN) at screening

Sponsors & Collaborators

• Prime Medicine, Inc.: lead

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 8, 2026
• First Posted: October 21, 2026
• Study Start: October 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): January 1, 2029
• Last Updated: October 21, 2026

Record last verified: 2026-10